Steroid hormones regulate many cellular and tissue functions. Progesterone, a 4-pregnene-3,20-dione derived from cholesterol, is a critical component of the female reproductive cycle. Serum plasma levels of progesterone oscillate during each cycle of ovulation. These oscillations help to mediate biochemical and molecular activity in target tissues and result in anatomical and morphological changes. The persistence of such changes are interdependant upon many unknown molecular or environmental factors.
Prior to ovulation, serum or intracellular cholesterol is converted to testosterone (T) in the theca interna of the ovary. Conversion of cholesterol to T is enhanced by luteinizing hormone (LH). In turn, follicle stimulating hormone (FSH) enhances the conversion of T to estradiol-17.beta. in the granulosa cell compartment. Following ovulation, the decrease in tissue LH levels and LH receptors in the corpus luteum results in conversion of cholesterol principally to progesterone. The surge in levels of progesterone results in feedback inhibition of LH and FSH synthesis in the pituitary and causes increased fluid secretion by endometrial glands of the uterus. If oocyte fertilization occurs, the corpus luteum continues to secrete progesterone to benefit fetal development. By the end of the first trimester progesterone synthesis rates within the placenta have increased and within the corpus luteum have diminished.
The molecular target of progesterone is the intracellular progesterone receptor (PR). The PR is present in the cytoplasm in a heterocomplex comprising several other proteins and factors termed the PR heterocomplex (PRC). The PR is maintained in an inactive form by molecular chaperones, immunophillins, and the heat shock proteins (hsp70, hsp90, hsp27, and p59 (hsp56), p48 and p23; Johnson, J. L. et al. (1994) Mol. Cell. Biol. 14:1956-1963). Active PR binds progesterone and translocates to the nucleus where it binds as a transcription factor to canonical DNA transcriptional elements present in progesterone-regulated genes. Progesterone-regulated genes have been implicated in differentiation and in the cell cycle (Moutsatsou, P and Sekeris, C. E. (1997) Ann. N.Y. Acad. Sci. 816:99-115).
The assembly of the PRC in vitro involves an ordered interaction between PR and at least eight components. For example, hsp70 binds to the PR and prevents interaction with its ligand; and hsp90 prevents intranuclear translocation by PR in the absence of progesterone (Kang. K. I. et al. (1994) Proc. Natl. Acad. Sci. 91:340-344). Conversely, chemical modification of hsp70 and hsp90 causes release of RP. Other unknown signals affect the interactions of hsp90 with p23 (Johnson, J. L. et al. (supra)).
p23 is a highly conserved protein detected in many higher metazoans, for example chicken and human, with no structural homology to other known proteins. p23 is a very hydrophobic protein with an aspartic acid-rich C-terminus and an observed isoelectric point of 4.5 to 5.2. The amino acid sequence predicts a protein with apparent molecular mass of 18.7 kDa, but p23 migrates on SDS-polyacrylamide gels at approximately 23 kDa. The size discrepancy is due to either decreased mobility or posttranslational chemical modification, for example, phosphorylation (Johnson, J. L. et al. (supra)).
Arrest of PRC assembly in vitro may be blocked by the selective hsp90 binding agent geldanamycin (GA). Intermediate PR complexes which include hsp90 and p23 but do not bind progesterone are formed in the presence of GA (Smith D. F. et al. (1995) Mol. Cell. Biol. 15:6804-6812). hsp70 binds the mutated tumor-suppressor gene p53 and has been associated with decreased nuclear localization of PR in tissue from node-negative breast tumors (Elledge, R. M. et al. (1994) Cancer Res. 54:3752-3757).
The discovery of a new human progesterone complex p23-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of neurological, reproductive, immunological, and neoplastic disorders.